Positive end-expiratory pressure modulates perfluorochemical evaporation from the lungs.

To study the effects of positive end-expiratory pressure (PEEP) level on perfluorochemical (PFC) elimination profiles (E(L)), 6 ml/kg of perflubron were instilled into healthy anesthetized rabbits. The ventilation strategy was to maintain constant minute ventilation (300 ml/kg/min) and mean airway pressure (7-8 cm H(2)O) while randomly changing the PEEP levels from 5 to 0, 1, 3, and 10 cm H(2)O, each for a period of 15 min. The PFC content in the expired gas was measured and the E(L) was calculated. There was a significant reduction in the E(L) when decreasing the PEEP levels from 5 to 0 cm H(2)O, but no differences were seen when the PEEP was increased from 5 to 10 cm H(2)O. The results indicate that PEEP levels influence PFC elimination profiles; therefore, the measurement of the E(L) and PEEP levels should be considered when optimizing supplemental PFCs during partial liquid ventilation.

Role of ventilation strategy on perfluorochemical evaporation from the lungs.

To study the effect of ventilation strategy on perfluorochemical (PFC) elimination profile (evaporative loss profile; E(L)), 6 ml/kg of perflubron were instilled into anesthetized normal rabbits. The strategy was to maintain minute ventilation (VE, in ml/min) in three groups: VE(L) (low-range VE, 208 +/- 2), VE(M) (midrange VE, 250 +/- 9), and VE(H) (high-range VE, 293 +/- 1) over 4 h. In three other groups, respiratory rate (RR, breaths/min) was controlled at 20, 30, or 50 with a constant VE and adjusted tidal volume. PFC content in the expired gas was measured, and E(L) was calculated. There was a significant VE- and time-dependent effect on E(L.) Initially, percent PFC saturation and loss rate decreased in the VE(H) > VE(M) > VE(L) groups, but by 3 h the lower percent PFC saturation resulted in a loss rate such that VE(H) < VE(M) < VE(L) at 4 h. For the groups at constant VE, there was a significant time effect on E(L) but no RR effect. In conclusion, E(L) profile is dependent on VE with little effect of the RR-tidal volume combination. Thus measurement of E(L) and VE should be considered for the replacement dosing schemes during partial liquid ventilation.

Perfluorochemical elimination from the lungs: effect of initial dose.

Liquid-assisted ventilation with perfluorochemical (PFC) has been beneficial in a variety of respiratory diseases in animals and humans. Although PFC evaporation from the lungs is in part dependent on ventilation strategy and positioning, guidelines for initial and replacement dosing are unclear. We hypothesized that PFC evaporative loss over time is dependent on the size of the initial dose. Juvenile rabbits (n = 18) were ventilated using constant animal position and ventilator strategy. PFC (perflubron: LiquiVent ) was instilled endotracheally, using four groups with initial doses of 2, 6, 12, and 17 mL/kg. A previously described thermal detector that measures PFC in expired gas was used to calculate loss rate, residual perflubron in the lung, and volume loss as a % of initial fill volume. There was a significant dose, time, and dose-time interaction such that evaporative loss was dependent on initial PFC volume and time after fill (P < 0.05). Evaporative loss rate decreased earlier at lower doses. The percentage of initial volume lost to evaporation over time was inversely related to dose and could not be predicted by decreasing % PFC saturations, independent of dose. Evaporative loss should be considered to optimize both the application of PFC to the lung and replacement dosing during partial liquid ventilation.

On-line techniques for perfluorochemical vapor sampling and measurement.

The authors developed a compact gas sampling and perfluorochemical (PFC) measuring system for use in total and partial liquid ventilation systems, based on a precision two-thermistor thermal detector (TD). They describe the sensitivity and linearity of their on-line method for PFC analysis of expired gases and show how it may be used in partial liquid ventilation studies for determining PFC saturation and loss. Gas is sampled for a short time from a breathing circuit through a heated tube at a selectable point in the breathing cycle. Inspiration is sensed by a pressure transducer. The sample of gas is pulled into the heated (48 degrees C) thermistor chamber by suction and held there while the cooling effect of the vapor changes the thermistor temperature. Dry air in another chamber affects a second thermistor, and the difference of these responses is amplified. The raw signal is corrected for the effects of varying O2 levels by a fuel cell. This signal is sampled and held and displayed on a front panel display. Calibration is performed in percentage saturation at 37 degrees C using the PFC in use at that temperature, or another standard such as O2. In-vitro testing showed a linear response in the thermal detector device (R2 = 0.99) over the range of vapor pressures tested (0-14) mmHg) and was reproducible to within 3%. When electronically corrected for changes in O2 concentration, there was less than a 2% change in PFC saturation. The TD responses to CO2 (R2 = 0.99) and water vapor (R2 = 1.0) were linear and approximately equal and opposite over the normal operating ranges of expired gases. In-vivo results in rabbits showed a significant (R2 = 0.73; p < 0.01) correlation between the auto-sampler and manual collection modes for determination of PFC in expired gas.

Current status of liquid ventilation.

Perfluorochemical liquid has been used experimentally to enhance mechanical ventilation for the past 30 years. Liquid ventilation is one of the most extensively studied revolutionary medical therapies being considered for use in practice. Since 1989, when the first human neonates were treated with perfluorochemical liquid, more than 500 human patients--neonate, pediatric, and adult--have been treated with liquid ventilation as part of clinical trials. However, most of the clinically relevant information known to the medical field about liquid ventilation still comes from the laboratory. This paper seeks to briefly present current information available from studies involving liquid ventilation, both laboratory-based and clinical trials, as well as to inform the reader on patient management. In addition, we attempt to elucidate future directions.

Comparison of perfluorochemical fluids used for liquid ventilation: effect of endotracheal tube flow resistance.

Neonatal endotracheal tubes with small inner diameters are associated with increased resistance regardless of the medium used for assisted ventilation. During liquid ventilation (LV) reduced interfacial tension and pressure drop along the airways result in lower alveolar inflation pressure compared with gas ventilation (GV). This is possible by optimizing liquid ventilation strategies to overcome the resistive forces associated with liquid density (rho) and viscosity (mu) of these fluids. Knowledge of the effect of rho, mu, and endotracheal tube (ETT) size on resistance is essential to optimize LV strategies. To evaluate these physical properties, three perfluorochemical (PFC) fluids with a range of kinematic viscosities (FC-75 = 0.82, LiquiVent = 1.10, APF-140 = 2.90) and four different neonatal ETT tubes (Mallincrokdt Hi-Lo Jet ID 2.5, 3.0, 3.5, and 4.0 mm) were studied. Under steady-state flow, flow and pressure drop across the ETTs were measured simultaneously. Resistance was calculated by dividing pressure drop by flow, and both pressure-flow and resistance-flow relationships were plotted. Also, pressure drop and resistance were each plotted as a function of kinematic viscosity at flows of 0.01 L.s-1 for all four ETT sizes. Data demonstrated a quadratic relationship with respect to pressure drop versus flow, and a linear relationship with resistance versus flow: both were significantly correlated (R = 0.92; P < 0.01) and were inversely related to ETT size. Additionally, there was a significant correlation between pressure drop or resistance and kinematic viscosity (R = 0.99; P < 0.01). For LV in neonates these data can be used to select the optimum ETT size and PFC liquid depending OR the chosen ventilation strategy.

Enhanced distribution of adenovirus-mediated gene transfer to lung parenchyma by perfluorochemical liquid.

Although gene therapy holds great promise for the treatment of inherited and acquired diseases of the lung, a number of issues including efficient delivery and distribution of genes to pulmonary target cells must still be addressed. In this study we evaluated the use of perfluorochemical (PFC) liquid as a vehicle for delivery of recombinant adenovirus (AdCBlacZ) to lungs of juvenile rabbits. Virus was instilled into trachea of rabbits, and 4 days later the lungs were removed, cut into multiple pieces, and assayed for beta-galactosidase (beta-Gal) activity. Total lung expression of the beta-Gal reporter gene was increased two- to three-fold by instillation of the virus (10(11) particles/kg body weight) in saline (1.5 ml/kg) simultaneously with perflubron liquid (15 ml/kg) compared to virus+saline alone (control). Uniformity of beta-Gal activity between lobes was significantly improved by the PFC liquid. In perflubron-treated lungs approximately 45% of the lung pieces had beta-Gal-specific activity values within 50-150% of the mean specific activity for the total lung, compared to only approximately 15% of the pieces in control lungs. More of total lobar beta-Gal activity was recovered in the distal lung tissue (approximately two-fold greater than controls, p < 0.05). Morphological assessment of X-Gal-stained, fresh-frozen lung sections showed increased levels and more complete staining of alveolar wall cells in the PFC group. These data indicate that the PFC liquid perflubron enhances distribution of virus-mediated gene expression to the lung parenchyma in healthy rabbits. PFC liquid may be a useful treatment vehicle for accessing distal spaces of the damaged or diseased lung.

Partial liquid ventilation in critically ill infants receiving extracorporeal life support. Philadelphia Liquid Ventilation Consortium.

OBJECTIVES: To demonstrate that a period of partial liquid ventilation (PLV) with perflubron improves pulmonary function, without adverse events, in a select group of critically ill infants receiving extracorporeal life support (ECLS) with a high likelihood of mortality. METHODS: This was an open-label, noncontrolled, phase I and II trial of PLV in two infants with congenital diaphragmatic hernia and four infants with acute respiratory distress syndrome (ARDS) who were failing to improve while receiving ECLS. PLV was performed by instilling and maintaining a functional residual capacity of sterile perflubron for 4 to 96 hours. RESULTS: Four infants were successfully weaned off ECLS for at least 3 days, and two infants (both with ARDS) are long-term survivors after PLV. All infants demonstrated lung recruitment and improved lung compliance, and there were no adverse events related to PLV. CONCLUSIONS: The study suggests that perflubron PLV is safe, improves lung function, and recruits lung volume in critically ill infants receiving ECLS. PLV therapy for infants with ARDS seems to have a great deal of promise. Based on this and other phase I and II trials, studies of PLV on selected full-term infants before ECLS have been initiated.

Pulmonary administration of gentamicin during liquid ventilation in a newborn lamb lung injury model.

OBJECTIVES: Newborns with pulmonary infection frequently present with acute lung injury leading to ventilation/perfusion abnormalities in which intravenous delivery of antibiotics to the lung can be suboptimal. Tidal liquid ventilation (TLV) has been shown to be an effective means for delivering drugs directly to the pulmonary system. The objective of this study was to compare, with lung injury, antibiotic delivery achieved by conventional techniques (gas ventilation and intravenous gentamicin) with that using pulmonary administration of drug (PAD) during TLV. METHODS: Twelve newborn lambs with an acid lung injury were randomized to receive gentamicin either intravenously during gas ventilation or via PAD during TLV using LiquiVent (Alliance Pharmaceutical Corporation, San Diego, CA, and Hoechst-Marion Roussel, Bridgewater, NJ) perfluorochemical. Gentamicin (5 mg/kg) was administered over 1 minute, and serum levels were obtained at 15-minute intervals. Arterial blood gases and pulmonary mechanics were measured. Ventilation efficiency index and arterial/alveolar oxygen ratio were calculated. Lung-tissue gentamicin levels were measured 4 hours after administration and corrected to dry weight. RESULTS: Serum gentamicin levels were similar in both groups. Lung gentamicin levels (micrograms/g) were significantly higher for TLV. Also, TLV resulted in significantly more of the total delivered dose in the lung after 4 hours. Ventilation efficiency index and arterial/alveolar oxygen ratios were significantly higher for TLV. CONCLUSIONS: In this lung injury model, both methods achieved equivalent serum gentamicin levels with higher lung levels using PAD during TLV. This study suggests that TLV may provide an effective vehicle for gentamicin delivery in infants with severe pulmonary infection and ventilation/perfusion abnormalities.

Use of liquid ventilation with perflubron during extracorporeal membrane oxygenation: chest radiographic appearances.

PURPOSE: To assess the effectiveness of performing liquid ventilation with perflubron in neonates with severe respiratory failure or pulmonary hypertension who receive extracorporeal membrane oxygenation (ECMO) life support. MATERIALS AND METHODS: We studied an infant (aged 1 month) and a neonate with respiratory failure who underwent ECMO and liquid ventilation with perflubron, which was slowly instilled via an endotracheal tube (in the infant, 40 mL for more than 1 hour; in the neonate, 28 mL within 1 hour). RESULTS: The infant survived termination of ECMO support and has been breathing room air since 6 months of age. The neonate died soon after ECMO support was withdrawn. CONCLUSION: A minority of neonates or infants with severe respiratory failure or pulmonary hypertension do not respond adequately to treatment with ECMO and are almost certain to die with termination of ECMO support. Liquid ventilation with perflubron offers a potential salvage therapy in this patient population. In addition, perflubron is a good contrast agent to use in the evaluation of neonatal pulmonary abnormalities.

Neonatal endotracheal tubes: variation in airway resistance with different perfluorochemical liquids.

To evaluate the effect of the physical properties of density and viscosity on airway resistance, three perfluorochemical fluids (PFCs) were used: FC-75, Liquivent, and APF-140. Using two different endotracheal tubes (ETT) (3.0mm ID and 4.0mm internal diameter (ID)), the three fluids were studied at steady state flow conditions over a range that approximated peak flow required for liquid ventilation of neonatal lambs (0.005-0.02 l/sec). The slope of airway resistance (Raw)-flow curves and absolute values of Raw for the 3 PFC liquids were higher for the 3.0 ETT compared to the 4.0 ETT. The 3.0 ETT demonstrated resistance changes that were dependent on flow, density and viscosity. The 4.0 ETT showed a resistance-flow relationship that was relatively less dependent on flow, density and viscosity.

Effect of enteral gavage feeding rate on pulmonary functions of very low birth weight infants.

To compare the effects of intermittent and continuous feedings on pulmonary function, we studied 24 very low birth weight neonates (mean +/- SD: birth weight, 1.2 +/- 0.3 kg; gestational age, 30.5 +/- 1.1 weeks) at 2 to 4 weeks of age. All infants had a previous diagnosis of respiratory distress syndrome but no subsequent diagnosis of bronchopulmonary dysplasia. Pulmonary mechanics were measured before the beginning of intermittent or continuous feedings and 10 minutes after each meal was completed. Twelve infants were randomly assigned to intermittent and 12 to continuous feedings. These infants had similar birth weight, gestational age, study age, and baseline lung function. After intermittent feedings, there was a significant decrease in tidal volume (38%), minute ventilation (44%), and dynamic compliance (28%), whereas pulmonary resistance increased significantly (100%). In comparison, the pulmonary function data remained unchanged after continuous feedings. These data demonstrate that intermittent feeding of very low birth weight infants can lead to airflow and respiratory instability. These adverse effects appear to be dependent on the rate that feedings are administered. A slower pace of feeding may be more advantageous for infants prone to respiratory instability.

Multichannel polysomnographic recording for evaluation of infant apnea.

The preceding discussion has consisted of a review of the technical and clinical aspects of pediatric multichannel recordings, which have become a widely used procedure in the clinical evaluation of infants with various apnea syndromes. It has been shown that multichannel recordings are superior to two-channel pneumocardiograms. Multichannel recordings should therefore be considered in all infants with unexplained episodes of apnea, bradycardia or cyanosis, in order to clarify the type of apnea and to rule out underlying conditions such as gastroesophageal reflux or seizures. The role of multichannel recording in predicting the risk of further apnea and SIDS, however, remains questionable. The clinical introduction of documented monitoring in the home setting with integrated pulse oximetry and a method for monitoring respiratory airflow might help to identify those infants at risk for apnea and SIDS in the future (see article by Weese-Mayer and Silvestri). Nevertheless, multichannel recordings in the hospital have provided a useful tool in the initial evaluation of many infants with infant apnea, and, for SIDS research, they have been useful for evaluating the complex autonomic control mechanisms during sleep and wakefulness.

Pseudoreflux syndrome-increased periodic breathing during the neonatal period presenting as feeding-related difficulties.

Sixteen infants who presented with symptoms suggestive of gastroesophageal reflux (GER)-associated apnea were evaluated at the Breathing Disorder Center of the Children's Hospital of Philadelphia. These neonates had a history of occasional emesis and an apparent life-threatening event (ALTE) that occurred while awake which was similar to the presentation of a group of infants previously described. Evaluation of the present group of infants however, revealed increased periodic breathing (12.1 +/- 1.8 SEM% of total sleep time) as opposed to the obstructive apnea that was typically seen with GER. Pathologic gastroesophageal reflux could not be diagnosed in relationship to apneic events. Infants who present during the first month of life with symptoms suggestive of GER-associated apnea should have careful evaluation of reflux and respiratory patterns to confirm the correct diagnosis. Because of the similarities of these infants to the GER group, we have called their disorder pseudoreflux.

Pneumograms in premature infants: a study of longitudinal data.

In order to define longitudinal data in premature infants, impedance pneumograms were performed weekly on 23 healthy premature infants. Studies were performed while infants remained hospitalized and at the discretion of the attending physician following discharge. A total of 97 studies were obtained on the study group. The recordings were analyzed for percentage of sleep time spent in periodic breathing, apnea density, and duration of longest apneic pause. Infants in this study demonstrated decreased percent of periodic breathing and decreased apnea density with increased maturation; longest pause per recording was independent of postconceptional age. Results from this study provide data to assist in the evaluation of pneumograms in the premature infant.

Pulmonary mechanics in preterm neonates with respiratory failure treated with high-frequency oscillatory ventilation compared with conventional mechanical ventilation.

Pulmonary mechanics were measured in 43 preterm neonates (mean +/- SD values of birth weight 1.2 +/- 0.3 kg, gestational age 30 +/- 2 weeks) with respiratory failure who were concurrently randomly assigned to receive conventional mechanical ventilation (n = 22) or high-frequency ventilation (n = 21). The incidence of bronchopulmonary dysplasia was comparable in the two groups (high-frequency ventilation 57%, conventional ventilation 50%). Pulmonary functions were determined at 0.5, 1.0, 2.0, and 4.0 weeks postnatal ages. Data were collected while subjects were in a nonsedated state during spontaneous breathing. These sequential data show similar patterns of change in pulmonary mechanics during high-frequency ventilation and conventional mechanical ventilation irrespective of gestational age, birth weight stratification, or bronchopulmonary dysplasia. There was no significant difference in the pulmonary functions with either mode of ventilation during the acute phase (less than or equal to 4 weeks) of respiratory disease. When evaluated by the clinical diagnosis of bronchopulmonary dysplasia, the pulmonary data suggested a less severe dysfunction in the high-frequency oscillatory ventilation-treated bronchopulmonary dysplasia group compared with the conventional mechanical ventilation-treated group. These results indicate that high-frequency oscillatory ventilation in preterm neonates does not reduce the risk of acute lung injury; however, the magnitude of the pulmonary dysfunction in the first 2 weeks of life merits a reevaluation.

A randomized placebo-controlled study to evaluate the effects of oral albuterol on pulmonary mechanics in ventilator-dependent infants at risk of developing BPD.

Albuterol is a specific beta-2 agonist that has been reported to be effective in treating infants and children with bronchospastic pulmonary disease. The use of oral albuterol has not been investigated in patients with bronchopulmonary dysplasia (BPD). Thirty premature infants were randomized to receive oral albuterol (0.15 mg/kg/dose q8h) or a volume- and color-matched placebo (D5/W). Pulmonary functions were evaluated at baseline and at 48 and 96 hours after entry to the study. The study was also designed for crossover from placebo to albuterol or albuterol to caffeine in the event that the infant's total pulmonary resistance did not improve at the time of the 48 hour pulmonary function evaluation. Heart rate and respiratory rate showed a statistically significant but clinically unimportant increase in the albuterol-treated infants. There were no significant differences noted in systolic or diastolic blood pressure. Percent improvement in the pulmonary function indices were calculated from baseline to 48 hours and from baseline to 96 hours for the placebo and albuterol-treated groups. The results indicate that at 48 hours there were statistically significant improvements in total resistance (14.5%), inspiratory resistance (10.8%), and expiratory resistance (12.9%) in the albuterol-treated infants as compared to the spontaneous deterioration of the same values by 25%, 81%, and 11%, respectively, in the placebo-treated infants. In conclusion, oral albuterol therapy of 48 hours duration improved pulmonary resistance without major cardiovascular side effects in ventilator-dependent premature infants.

Changes in pulmonary mechanics following caffeine administration in infants with bronchopulmonary dysplasia.

The effects of caffeine upon pulmonary mechanics were measured in 16 infants with bronchopulmonary dysplasia (BPD). Pulmonary function tests were performed immediately prior to and 1 hour following a dose of 10 mg/kg of caffeine. A 37% increase in minute ventilation (mean +/- SEM; 436.6 +/- 26.3 to 580.8 +/- 30.7 ml/min/kg) was seen with caffeine administration (P less than 0.001), primarily from a 42% increase in tidal volume (6.2 +/- 0.4 to 8.5 +/- 0.4 ml/kg) (P less than 0.001). Total lung resistance decreased by 20% (134.6 + 24.2 to 105.3 +/- 20.1 cmH2O/L/sec) (P = 0.01), and total pulmonary compliance improved by 47% (0.642 +/- 0.104 to 0.908 +/- 0.190 ml/cmH2O/kg) (P less than 0.01). In five matched control infants with BPD, no effects of placebo upon pulmonary mechanics were detected. Since caffeine has a wide therapeutic index with few side effects, it may be an effective adjunct in the treatment of infants with BPD.

Ventilatory response to combined high frequency jet ventilation and conventional mechanical ventilation for the rescue treatment of severe neonatal lung disease.

High frequency jet ventilation (HFJV) was used to treat 176 infants who were either failing to respond to conventional mechanical ventilation (CMV) or demonstrating pulmonary air leak. The median birthweight for infants treated with HFJV was 1530 g, median gestational age was 31 weeks. Median duration of therapy with HFJV was 3.0, with a range of 0.1 to 27 days. During the first 24 hours of treatment, mean airway pressure decreased from 16.2 +/- 0.3 (Mean +/- SEM) cmH2O to 12.2 +/- 0.3 cmH2O, while mean PaO2 increased from 65.3 +/- 3.0 torr to 93.3 +/- 3.0 torr during the same time period. Simultaneously, mean PaCO2 decreased from 46.4 +/- 1.5 torr to 36.6 +/- 1.0 torr, although peak inflating pressure decreased from 34.3 +/- 0.7 cmH2O to 30.1 +/- 0.8 cmH2O. Ninety-five (54%) infants treated with HFJV survived. Of 123 infants with RDS 75 (61%) survived. The rate of complications for HFJV patients was similar to that seen with CMV in our nursery. This study suggests that HFJV provides improved oxygenation and ventilation of infants at lower mean and peak pressures compared to conventional mechanical ventilation. HFJV combined with CMV may be a valuable adjunct to therapy in infants with severe lung disease.

Continuous intracranial pressure monitoring and serial electroencephalographic recordings in severely asphyxiated term neonates.

We report our observations from intensive intracranial pressure (ICP) monitoring and serial clinical neurologic and electroencephalographic examinations in ten asphyxiated full-term neonates, of whom five died and at least two survivors had multiple severe neurologic handicaps. Direct measurements of ICP were obtained by a newly developed infant subarachnoid bolt and/or a transfontanelle pressure transducer. Simultaneous ICPs were recorded and correlated when possible. We noted a dependence of transfontanelle ICP values on application technique and force. In infants with no bleeding diathesis, the subarachnoid bolt was safe and no complications were encountered. Only six infants experienced pathologic elevations of ICP following birth asphyxia, and of these infants only two had sustained, marked increases of ICP. We also noted abundant fluctuations of cerebral perfusion pressure (mean arterial blood pressure minus ICP), but the majority of fluctuations were accounted for by mean arterial pressure changes rather than ICP changes. We found no deterioration of clinical neurologic function as measured by serial mental status examinations and electroencephalogram samples at the time the maximum ICP was measured. We also noted very little change in ICP during most electrographic seizures. In these infants ICP did increase after birth but major ICP elevations were uncommon and did not appear to introduce any acute functional neurologic disturbances. Most changes in cerebral perfusion pressure were attributed to blood pressure rather than ICP changes. It appears unlikely that cerebral edema and elevated ICP play a major role in determining neurologic outcome in some asphyxiated term infants.